title: Usage of adenovirus expressing thymidine kinase mediated hepatocellular damage for enabling mouse liver repopulation with allogenic or xenogenic hepatocytes.
abstract: It has been shown that the liver of immunodeficient mice can be efficiently repopulated with human hepatocytes when subjected to chronic hepatocellular damage. Mice with such chimeric livers represent useful reagents for medical and clinical studies. However all previously reported models of humanized livers are difficult to implement as they involve cross-breeding of immunodeficient mice with mice exhibiting genetic alterations causing sustained hepatic injury. In this paper we attempted to create chimeric livers by inducing persistent hepatocellular damage in immunodeficient Rag2(-/-) γc(-/-) mice using an adenovirus encoding herpes virus thymidine kinase (AdTk) and two consecutive doses of ganciclovir (GCV). We found that this treatment resulted in hepatocellular damage persisting for at least 10 weeks and enabled efficient engraftment and proliferation within the liver of either human or allogenic hepatocytes. Interestingly, while the nodules generated from the transplanted mouse hepatocytes were well vascularized, the human hepatocytes experienced progressive depolarization and exhibited reduced numbers of murine endothelial cells inside the nodules. In conclusion, AdTk/GCV-induced liver damage licenses the liver of immunodeficient mice for allogenic and xenogenic hepatocyte repopulation. This approach represents a simple alternative strategy for chimeric liver generation using immunodeficient mice without additional genetic manipulation of the germ line.
authors.affiliation: Gene Therapy and Hepatology Area, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moreno
authors.forename: Anangi
authors.initials: A
authors.lastname: Balasiddaiah
authors.forename: Oscar
authors.initials: O
authors.lastname: Lamas
authors.forename: Cedric
authors.initials: C
authors.lastname: Duret
authors.forename: Leire
authors.initials: L
authors.lastname: Neri
authors.forename: Laura
authors.initials: L
authors.lastname: Guembe
authors.forename: Miguel
authors.initials: M
authors.lastname: Galarraga
authors.forename: Esther
authors.initials: E
authors.lastname: Larrea
authors.forename: Martine
authors.initials: M
authors.lastname: Daujat-Chavanieu
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntane
authors.forename: Patrick
authors.initials: P
authors.lastname: Maurel
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Riezu
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.forename: Rafael
authors.initials: R
authors.lastname: Aldabe
mesh_terms: D000256:Adenoviridae / Q000378:metabolism*; D000418:Albumins / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015774:Ganciclovir / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006509:Hepatitis B / Q000473:pathology; D006526:Hepatitis C / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013937:Thymidine Kinase / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
chemical_list: D000418:Albumins; D004268:DNA-Binding Proteins; D053631:Interleukin Receptor Common gamma Subunit; C064655:V(D)J recombination activating protein 2; D049452:Green Fluorescent Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir